Argatroban

CLINICAL PHARMACOLOGY

Mechanism Of Action

Argatroban is a direct thrombin
inhibitor that reversibly binds to the thrombin active site. Argatroban does
not require the co-factor antithrombin III for antithrombotic activity.
Argatroban exerts its anticoagulant effects by inhibiting thrombin-catalyzed or
-induced reactions, including fibrin formation; activation of coagulation
factors V, VIII, and XIII; activation of protein C; and platelet aggregation.

Argatroban inhibits thrombin
with an inhibition constant (Ki) of 0.04 μM. At therapeutic
concentrations, argatroban has little or no effect on related serine proteases
(trypsin, factor Xa, plasmin, and kallikrein).

Argatroban is capable of
inhibiting the action of both free and clot-associated thrombin.

Pharmacodynamics

When argatroban is administered
by continuous infusion, anticoagulant effects and plasma concentrations of
argatroban follow similar, predictable temporal response profiles, with low
intersubject variability. Immediately upon initiation of argatroban infusion,
anticoagulant effects are produced as plasma argatroban concentrations begin to
rise. Steady-state levels of both drug and anticoagulant effect are typically
attained within 1 to 3 hours and are maintained until the infusion is
discontinued or the dosage adjusted. Steady-state plasma argatroban
concentrations increase proportionally with dose (for infusion doses up to 40
mcg/kg/min in healthy subjects) and are well correlated with steady-state
anticoagulant effects. For infusion doses up to 40 mcg/kg/min, argatroban
increases in a dose-dependent fashion, the activated partial thromboplastin
time (aPTT), the activated clotting time (ACT), the prothrombin time (PT), the
International Normalized Ratio (INR), and the thrombin time (TT) in healthy
volunteers and cardiac patients. Representative steady-state plasma argatroban
concentrations and anticoagulant effects are shown below for argatroban
infusion doses up to 10 mcg/kg/min (see Figure 1).

Effect on International
Normalized Ratio (INR)

Because argatroban is a direct
thrombin inhibitor, coadministration of argatroban and warfarin produces a
combined effect on the laboratory measurement of the INR. However, concurrent
therapy, compared to warfarin monotherapy, exerts no additional effect on
vitamin K–dependent factor Xa activity.

The relationship between INR on
co-therapy and warfarin alone is dependent on both the dose of argatroban and
the thromboplastin reagent used. This relationship is influenced by the
International Sensitivity Index (ISI) of the thromboplastin. Data for 2
commonly utilized thromboplastins with ISI values of 0.88 (Innovin, Dade) and
1.78 (Thromboplastin C Plus, Dade) are presented in Figure 2 for an argatroban
dose of 2 mcg/kg/min. Thromboplastins with higher ISI values than shown result
in higher INRs on combined therapy of warfarin and argatroban. These data are
based on results obtained in normal individuals [see WARNINGS AND
PRECAUTIONS, DOSAGE AND ADMINISTRATION].

Figure 2 demonstrates the
relationship between INR for warfarin alone and INR for warfarin coadministered
with argatroban at a dose of 2 mcg/kg/min. To calculate INR for warfarin alone
(INRW), based on INR for cotherapy of warfarin and argatroban (INRWA), when the
argatroban dose is 2 mcg/kg/min, use the equation next to the appropriate
curve. Example: At a dose of 2 mcg/kg/min and an INR performed with
Thromboplastin A, the equation 0.19 + 0.57 (INRWA) = INRW would allow a
prediction of the INR on warfarin alone (INRW). Thus, using an INRWA value of 4
obtained on combined therapy: INRW = 0.19 + 0.57 (4) = 2.47 as the value for
INR on warfarin alone. The error (confidence interval) associated with a
prediction is ± 0.4 units. Similar linear relationships and prediction errors
exist for argatroban at a dose of 1 mcg/kg/min. Thus, for argatroban doses of 1
or 2 mcg/kg/min, INRW can be predicted from INRWA. For argatroban doses greater
than 2 mcg/kg/min, the error associated with predicting INRW from INRWA is ± 1.
Thus, INRW cannot be reliably predicted from INRWA at doses greater than 2
mcg/kg/min.

Pharmacokinetics

Distribution

Argatroban distributes mainly
in the extra cellular fluid as evidenced by an apparent steady-state volume of
distribution of 174 mL/kg (12.18 L in a 70 kg adult). Argatroban is 54% bound
to human serum proteins, with binding to albumin and α1-acid glycoprotein
being 20% and 34%, respectively.

Metabolism

The main route of argatroban
metabolism is hydroxylation and aromatization of the 3methyltetrahydroquinoline
ring in the liver. The formation of each of the 4 known metabolites is
catalyzed in vitro by the human liver microsomal cytochrome P450 enzymes
CYP3A4/5. The primary metabolite (M1) exerts 3-to 5-fold weaker anticoagulant
effects than argatroban. Unchanged argatroban is the major component in plasma.
The plasma concentrations of M1 range between 0% and 20% of that of the parent
drug. The other metabolites (M2 to M4) are found only in very low quantities in
the urine and have not been detected in plasma or feces. These data, together
with the lack of effect of erythromycin (a potent CYP3A4/5 inhibitor) on
argatroban pharmacokinetics, suggest that CYP3A4/5-mediated metabolism is not
an important elimination pathway in vivo.

Total body clearance is
approximately 5.1 mL/kg/min (0.31 L/kg/hr) for infusion doses up to 40
mcg/kg/min. The terminal elimination half-life of argatroban ranges between 39
and 51 minutes.

There is no interconversion of
the 21–(R):21–(S) diastereoisomers. The plasma ratio of these diastereoisomers
is unchanged by metabolism or hepatic impairment, remaining constant at 65:35
(± 2%).

Excretion

Argatroban is excreted
primarily in the feces, presumably through biliary secretion. In a study in
which 14Cargatroban (5 mcg/kg/min) was infused for 4 hours into
healthy subjects, approximately 65% of the radioactivity was recovered in the
feces within 6 days of the start of infusion with little or no radioactivity
subsequently detected. Approximately 22% of the radioactivity appeared in the
urine within 12 hours of the start of infusion. Little or no additional urinary
radioactivity was subsequently detected. Average percent recovery of unchanged
drug, relative to total dose, was 16% in urine and at least 14% in feces.

Special Populations

Hepatic Impairment

The dosage of argatroban should
be decreased in patients with hepatic impairment [seeDOSAGE AND
ADMINISTRATION and WARNINGS AND PRECAUTIONS]. Patients with hepatic
impairment were not studied in percutaneous coronary intervention (PCI) trials.
At a dose of 2.5 mcg/kg/min, hepatic impairment is associated with decreased
clearance and increased elimination half-life of argatroban (to 1.9 mL/kg/min
and 181 minutes, respectively, for patients with a Child-Pugh score > 6).

Use of argatroban was evaluated
in a study of 12 patients with stable end-stage renal disease undergoing
chronic intermittent hemodialysis. Argatroban was administered at a rate of 2
to 3 mcg/kg/min (begun at least 4 hours prior to dialysis) or as a bolus dose
of 250 mcg/kg at the start of dialysis followed by a continuous infusion of 2
mcg/kg/min. Although these regimens did not achieve the goal of maintaining ACT
values at 1.8 times the baseline value throughout most of the hemodialysis
period, the hemodialysis sessions were successfully completed with both of
these regimens. The mean ACTs produced in this study ranged from 1.39 to 1.82
times baseline, and the mean aPTTs ranged from 1.96 to 3.4 times baseline. When
argatroban was administered as a continuous infusion of 2 mcg/kg/min prior to
and during a 4-hour hemodialysis session, approximately 20% was cleared through
dialysis.

Age, Gender

There are no clinically
significant effects of age or gender on the pharmacokinetics or
pharmacodynamics (e.g., aPTT) of argatroban in adults.

Drug-Drug Interactions

Digoxin

In 12 healthy volunteers,
intravenous infusion of argatroban (2 mcg/kg/min) over 5 days (study days 11 to
15) did not affect the steady-state pharmacokinetics of oral digoxin (0.375 mg
daily for 15 days).

Erythromycin

In 10 healthy subjects, orally administered erythromycin
(a potent inhibitor of CYP3A4/5) at 500 mg four times daily for 7 days had no
effect on the pharmacokinetics of argatroban at a dose of 1 mcg/kg/min for 5
hours. These data suggest oxidative metabolism by CYP3A4/5 is not an important
elimination pathway in vivo for argatroban.

Clinical Studies

Heparin-Induced Thrombocytopenia

The safety and efficacy of argatroban were evaluated in
an historically controlled efficacy and safety study (Study 1) and a follow-on
efficacy and safety study (Study 2). These studies were comparable with regard
to study design, study objectives, dosing regimens as well as study outline,
conduct, and monitoring.

In these studies, 568 adult patients were treated with
argatroban and 193 adult patients made up the historical control group.
Patients had a clinical diagnosis of heparin-induced thrombocytopenia, either
without thrombosis (HIT) or with thrombosis (HITTS [heparin-induced
thrombocytopenia and thrombosis syndrome]) and were males or non-pregnant
females between the ages of 18 and 80 years old. HIT/HITTS was defined by a
fall in platelet count to less than 100,000/μL or a 50% decrease in platelets
after the initiation of heparin therapy with no apparent explanation other than
HIT. Patients with HITTS also had an arterial or venous thrombosis documented
by appropriate imaging techniques or supported by clinical evidence such as
acute myocardial infarction, stroke, pulmonary embolism, or other clinical
indications of vascularocclusion. Patients who had documented histories of
positive heparin-dependent antibody tests without current thrombocytopenia or
heparin challenge (e.g., patients with latent disease) were also included if
they required anticoagulation.

These studies did not include patients with documented
unexplained aPTT > 200% of control at baseline, documented coagulation
disorder or bleeding diathesis unrelated to HIT, a lumbar puncture within the
past 7 days or a history of previous aneurysm, hemorrhagic stroke, or a
thrombotic stroke within the past 6 months unrelated to HIT.

The initial dose of argatroban was 2 mcg/kg/min. Two
hours after the start of the argatroban infusion, an aPTT level was obtained
and dose adjustments were made (up to a maximum of 10 mcg/kg/min) to achieve a
steady-state aPTT value that was 1.5 to 3 times the baseline value, not to
exceed 100 seconds. Overall the mean aPTT level for HIT and HITTS patients
during the argatroban infusion increased from baseline values of 34 and 38
seconds, respectively, to 62.5 and 64.5 seconds, respectively.

The primary efficacy analysis was based on a comparison
of event rates for a composite endpoint that included death (all causes),
amputation (all causes) or new thrombosis during the treatment and follow-up
period (study days 0 to 37). Secondary analyses included evaluation of the
event rates for the components of the composite endpoint as well as time-to-event
analyses.

In Study 1, a total of 304 patients were enrolled as
follows: active HIT (n = 129), active HITTS (n = 144), or latent disease (n =
31). Among the 193 historical controls, 139 (72%) had active HIT, 46 (24%) had
active HITTS, and 8 (4%) had latent disease. Within each group, those with
active HIT and those with latent disease were analyzed together. Positive
laboratory confirmation of HIT/HITTS by the heparin-induced platelet
aggregation test or serotonin release assay was demonstrated in 174 of 304
(57%) argatroban-treated patients (i.e., in 80 with HIT or latent disease and
94 with HITTS) and in 149 of 193 (77%) historical controls (i.e., in 119 with
HIT or latent disease and 30 with HITTS). The test results for the remainder of
the patients and controls were either negative or not determined.

There was a significant improvement in the composite
outcome in patients with HIT and HITTS treated with argatroban versus those in
the historical control group (see Table 9). The components of the composite
endpoint are shown in Table 9.

a Death (all cause), amputation (all cause), or new
thrombosis within 37-day study period b Reported as the most severe outcome among the components of
composite endpoint (severity ra nking: death > amputation > new
thrombosis); patients may have had multiple outcomes.

Time-to-event analyses showed
significant improvements in the time-to-first event in patients with HIT or
HITTS treated with argatroban versus those in the historical control group. The
between-group differences in the proportion of patients who remained free of
death, amputation, or new thrombosis were statistically significant in favor of
argatroban by these analyses.

A time-to-event analysis for
the composite endpoint is shown in Figure 3 for patients with HIT and Figure 4 for
patients with HITTS.

Figure 3: Time to First
Event for the Composite Efficacy Endpoint: HIT Patients STUDY 1

*Censored indicates no clinical
endpoint (defined as death, amputation, or new thrombosis) was observed during
the follow-up period (maximum period of follow-up was 37 days).

Figure 4: Time to First
Event for the Composite Efficacy Endpoint: HITTS Patients STUDY 1

*Censored indicates no clinical
endpoint (defined as death, amputation, or new thrombosis) was observed during
the follow-up period (maximum period of follow-up was 37 days).

In Study 2, a total of 264
patients were enrolled as follows: HIT (n = 125) or HITTS (n = 139). There was
a significant improvement in the composite efficacy outcome for
argatroban-treated patients, versus the same historical control group from
Study 1, among patients having HIT (25.6% vs. 38.8%), patients having HITTS
(41% vs. 56.5%), and patients having either HIT or HITTS (33.7% vs. 43%).
Time-to-event analyses showed significant improvements in the time-to-first
event in patients with HIT or HITTS treated with argatroban versus those in the
historical control group. The between-group differences in the proportion of
patients who remained free of death, amputation, or new thrombosis were
statistically significant in favor of argatroban.

Anticoagulant Effect

In Study 1, the mean (± SE)
dose of argatroban administered was 2 ± 0.1 mcg/kg/min in the HIT arm and 1.9 ±
0.1 mcg/kg/min in the HITTS arm. Seventy-six percent of patients with HIT and
81% of patients with HITTS achieved a target aPTT at least 1.5-fold greater
than the baseline aPTT at the first assessment occurring on average at 4.6
hours (HIT) and 3.9 hours (HITTS) following initiation of argatroban therapy.
No enhancement of aPTT response was observed in subjects receiving repeated
administration of argatroban.

Platelet Count Recovery

In Study 1, 53% of patients
with HIT and 58% of patients with HITTS, had a recovery of platelet count by
Day 3. Platelet Count Recovery was defined as an increase in platelet count to
> 100,000/μL or to at least 1.5-fold greater than the baseline count
(platelet count at study initiation) by Day 3 of the study.

Percutaneous Coronary
Intervention (PCI) Patients With Or At Risk For HIT

In 3 similarly designed trials,
argatroban was administered to 91 patients with current or previous clinical
diagnosis of HIT or heparin-dependent antibodies, who underwent a total of 112
percutaneous coronary interventions (PCIs) including percutaneous transluminal
coronary angioplasty (PTCA), coronary stent placement, or atherectomy. Among
the 91 patients undergoing their first PCI with argatroban, notable ongoing or
recent medical history included myocardial infarction (n = 35), unstable angina
(n = 23), and chronic angina (n = 34). There were 33 females and 58 males. The
average age was 67.6 years (median 70.7, range 44 to 86), and the average
weight was 82.5 kg (median 81 kg, range 49 to 141).

Twenty-one of the 91 patients
had a repeat PCI using argatroban an average of 150 days after their initial
PCI. Seven of 91 patients received glycoprotein IIb/IIIa inhibitors. Safety and
efficacy were assessed against historical control populations who had been
anticoagulated with heparin.

All patients received oral
aspirin (325 mg) 2 to 24 hours prior to the interventional procedure. After
venous or arterial sheaths were in place, anticoagulation was initiated with a
bolus of argatroban of 350 mcg/kg via a large-bore intravenous line or through
the venous sheath over 3 to 5 minutes. Simultaneously, a maintenance infusion
of 25 mcg/kg/min was initiated to achieve a therapeutic activated clotting time
(ACT) of 300 to 450 seconds. If necessary to achieve this therapeutic range,
the maintenance infusion dose was titrated (15 to 40 mcg/kg/min) and/or an
additional bolus dose of 150 mcg/kg could be given. Each patient's ACT was
checked 5 to 10 minutes following the bolus dose. The ACT was checked as
clinically indicated. Arterial and venous sheaths were removed no sooner than 2
hours after discontinuation of argatroban and when the ACT was less than 160
seconds.

If a patient required
anticoagulation after the procedure, argatroban could be continued, but at a
lower infusion dose between 2.5 and 5 mcg/kg/min. An aPTT was drawn 2 hours
after this dose reduction and the dose of argatroban then was adjusted as
clinically indicated (not to exceed 10 mcg/kg/min), to reach an aPTT between 1.5
and 3 times baseline value (not to exceed 100 seconds).

In 92 of the 112 interventions
(82%), the patient received the initial bolus of 350 mcg/kg and an initial
infusion dose of 25 mcg/kg/min. The majority of patients did not require
additional bolus dosing during the PCI procedure. The mean value for the
initial ACT measurement after the start of dosing for all interventions was 379
sec (median 338 sec; 5th percentile-95th percentile 238 to 675 sec). The mean
ACT value per intervention over all measurements taken during the procedure was
416 sec (median 390 sec; 5th percentile-95th percentile 261 to 698 sec). About
65% of patients had ACTs within the recommended range of 300 to 450 seconds
throughout the procedure. The investigators did not achieve anticoagulation
within the recommended range in about 23% of patients. However, in this small
sample, patients with ACTs below 300 seconds did not have more coronary
thrombotic events, and patients with ACTs over 450 seconds did not have higher
bleeding rates.

Acute procedural success was
defined as lack of death, emergent coronary artery bypass graft (CABG), or
Q-wave myocardial infarction. Acute procedural success was reported in 98.2% of
patients who underwent PCIs with argatroban anticoagulation compared with 94.3%
of historical control patients anticoagulated with heparin (p = NS). Among the
112 interventions, 2 patients had emergency CABGs, 3 had repeat PTCAs, 4 had
non-Qwave myocardial infarctions, 3 had myocardial ischemia, 1 had an abrupt
closure, and 1 had an impending closure (some patients may have experienced
more than 1 event). No patients died.

Last reviewed on RxList: 12/30/2014
This monograph has been modified to include the generic and brand name in many instances.